The fetus of a diabetic mother (FDM) is at increased risk for morbidity and mortality. Our work and the work of others suggests strongly that fetal pancreatic, pituitary-adrenocortical and adrenomedullary systems play significant roles in these events. For example, it is generally accepted that maternal hyperglycemia leads to fetal hyperglycemia and in turn to fetal hyperinsulinemia which stimulates fetal growth and results in macrosomia. However, we know that fetal macrosomia is not universal. This may be explained, at least partly, by our earlier observation that fetal hypoxic stress, a probable occurrence in some diabetic pregnancies, stimulates catecholamine secretion which inhibits the insulin response to hyperglycemia. We propose then the general hypothesis that fetal pituitary-adrenocortical and adrenomedullary function may play significant roles in determining the response of the fetus to maternal diabetes and, in turn, that the effects of maternal diabetes play a significant role in altering the way in which these same pituitary-adrenocortical and adrenomedullary systems themselves develop and function. The proposed work is intended to investigate the multiple permutations of this hypothesis. Experiments will be conducted in fetal sheep 7 (or more) days after operative placement of peripheral and adrenal cannulas. This will allow the determination of plasma concentrations of pertinent substances and the direct measurement of adrenal secretion rates of catecholamines (medulla) and glucocorticoids (cortex). A diabetes- like state (fetal hyperglycemia) will be experimentally induced. The effects of this perturbation on fetal adrenal medullary and cortical development and function will be studied. The potential impact of diabetic pregnancy on the development of the fetal pancreas will be studied. In clinical terms, these studies will be pertinent to the capacity of the FDM to mount an appropriate adrenal response to stress, the occurrence of macrosomia vs. growth retardation in FDM, pulmonary development in FDM, the capacity of the infant of a diabetic mother to mount an effective glucose counter-regulatory response when deprived of excess maternal glucose, and the increased occurrence of glucose intolerance in the progeny of diabetic pregnancy.